Chemical biology investigation of a triple-action, smart-decomposition antimicrobial booster based-combination therapy against “ESKAPE” pathogens

Abstract

The global antibiotic resistance crisis necessitates urgent solutions. One innovative approach involves potentiating antibiotics and non-antibiotic drugs with adjuvants or boosters. A major drawback of these membrane-active boosters is their limited biocompatibility, as they struggle to differentiate between prokaryotic and eukaryotic membranes. This study reports the chemical biology investigation of a dual-action oligoamidine (OA1) booster with a glutathione-triggered decomposition mechanism. OA1, when combined with other antimicrobial molecules, exhibits a triple-targeting mechanism including cell membrane disruption, DNA targeting, and intracellular enzyme inhibition. This multi-targeting mechanism not only enhances the in vitro and in vivo eradication of antibiotic-resistant “ESKAPE” pathogens, but also suppresses the development of bacterial resistance. Furthermore, OA1 maintains its activity in bacterial cells by creating an oxidative environment, while it quickly decomposes in mammalian cells due to high glutathione levels. These mechanistic insights and design principles may provide a feasible approach to develop novel antimicrobial agents and effective anti-resistance combination therapies.